Using a dummy quantitative variable to deal with multiple affection categories in genetic linkage analysis

Some diseases which have a genetic contribution to aetiology do not demonstrate a clear correspondence between genotype and phenotype. A variety of different clinical syndromes may be thought to reflect the action of a gene, but the probability of affection conditional on genotype may vary between these different diagnostic categories. The normal approach of repeating linkage analyses several times using different diagnoses to define individuals as affected loses power in two ways: multiple testing must be allowed for, and the distinction between more and less extreme forms of affection is lost. It is shown that for fully dominant or recessive autosomal diseases it is straightforward to assign a quantitative value to each diagnostic category to obtain the desired ratio of the likelihoods of affection conditional on the three possible genotypes. The increased power provided by using this quantitative value in linkage analysis is demonstrated by application to simulated pedigrees containing cases of bipolar and unipolar affective disorder.